scholarly journals Reduced generation of lung tissue–resident memory T cells during infancy

2017 ◽  
Vol 214 (10) ◽  
pp. 2915-2932 ◽  
Author(s):  
Kyra D. Zens ◽  
Jun Kui Chen ◽  
Rebecca S. Guyer ◽  
Felix L. Wu ◽  
Filip Cvetkovski ◽  
...  
Keyword(s):  
T Cells ◽  
Memory T Cells ◽  
Respiratory Infections ◽  
Influenza Infection ◽  
Life Stage ◽  
Human Infant ◽  
Respiratory Pathogens ◽  
Infant Mouse ◽  
Adult Mice ◽  
Resident Memory T Cells

Infants suffer disproportionately from respiratory infections and generate reduced vaccine responses compared with adults, although the underlying mechanisms remain unclear. In adult mice, lung-localized, tissue-resident memory T cells (TRMs) mediate optimal protection to respiratory pathogens, and we hypothesized that reduced protection in infancy could be due to impaired establishment of lung TRM. Using an infant mouse model, we demonstrate generation of lung-homing, virus-specific T effectors after influenza infection or live-attenuated vaccination, similar to adults. However, infection during infancy generated markedly fewer lung TRMs, and heterosubtypic protection was reduced compared with adults. Impaired TRM establishment was infant–T cell intrinsic, and infant effectors displayed distinct transcriptional profiles enriched for T-bet–regulated genes. Notably, mouse and human infant T cells exhibited increased T-bet expression after activation, and reduction of T-bet levels in infant mice enhanced lung TRM establishment. Our findings reveal that infant T cells are intrinsically programmed for short-term responses, and targeting key regulators could promote long-term, tissue-targeted protection at this critical life stage.

scholarly journals CXCR6 regulates localization of tissue-resident memory CD8 T cells to the airways

2019 ◽  
Vol 216 (12) ◽  
pp. 2748-2762 ◽  
Author(s):  
Alexander N. Wein ◽  
Sean R. McMaster ◽  
Shiki Takamura ◽  
Paul R. Dunbar ◽  
Emily K. Cartwright ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Protective Immunity ◽  
Memory T Cells ◽  
Respiratory Pathogens ◽  
First Line ◽  
Memory Cd8 T Cells ◽  
Effector Functions ◽  
Signaling Axis ◽  
Resident Memory T Cells

Resident memory T cells (TRM cells) are an important first-line defense against respiratory pathogens, but the unique contributions of lung TRM cell populations to protective immunity and the factors that govern their localization to different compartments of the lung are not well understood. Here, we show that airway and interstitial TRM cells have distinct effector functions and that CXCR6 controls the partitioning of TRM cells within the lung by recruiting CD8 TRM cells to the airways. The absence of CXCR6 significantly decreases airway CD8 TRM cells due to altered trafficking of CXCR6−/− cells within the lung, and not decreased survival in the airways. CXCL16, the ligand for CXCR6, is localized primarily at the respiratory epithelium, and mice lacking CXCL16 also had decreased CD8 TRM cells in the airways. Finally, blocking CXCL16 inhibited the steady-state maintenance of airway TRM cells. Thus, the CXCR6/CXCL16 signaling axis controls the localization of TRM cells to different compartments of the lung and maintains airway TRM cells.

Brain-resident memory T cells generated early in life predispose to autoimmune disease in mice

2019 ◽  
Vol 11 (498) ◽  
pp. eaav5519 ◽  
Author(s):  
Karin Steinbach ◽  
Ilena Vincenti ◽  
Kristof Egervari ◽  
Mario Kreutzfeldt ◽  
Franziska van der Meer ◽  
...  
Keyword(s):  
T Cells ◽  
Autoimmune Disease ◽  
Early Life ◽  
Viral Infections ◽  
Memory T Cells ◽  
Epidemiological Studies ◽  
Critical Window ◽  
Adult Mice ◽  
Previous Infection ◽  
Resident Memory T Cells

Epidemiological studies associate viral infections during childhood with the risk of developing autoimmune disease during adulthood. However, the mechanistic link between these events remains elusive. We report that transient viral infection of the brain in early life, but not at a later age, precipitates brain autoimmune disease elicited by adoptive transfer of myelin-specific CD4+ T cells at sites of previous infection in adult mice. Early-life infection of mouse brains imprinted a chronic inflammatory signature that consisted of brain-resident memory T cells expressing the chemokine (C-C motif) ligand 5 (CCL5). Blockade of CCL5 signaling via C-C chemokine receptor type 5 prevented the formation of brain lesions in a mouse model of autoimmune disease. In mouse and human brain, CCL5+ TRM were located predominantly to sites of microglial activation. This study uncovers how transient brain viral infections in a critical window in life might leave persisting chemotactic cues and create a long-lived permissive environment for autoimmunity.

scholarly journals Augmented TCR-mediated signaling in infant T cells enables robust responses to respiratory virus infection

2021 ◽  
Author(s):  
Donna Farber ◽  
Puspa Thapa ◽  
Rebecca Guyer ◽  
Alexander Yang ◽  
Christopher Parks ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Influenza Infection ◽  
Life Stage ◽  
Cell Receptor ◽  
Human Infant ◽  
Transfer Model ◽  
Effector Cells ◽  
Immune Synapse

Abstract Infants require coordinated immune responses to prevent succumbing to multiple infectious challenges, particularly in the respiratory tract. The mechanisms by which infant T cells are functionally adapted for these responses are not well understood. Here, we demonstrate using an in vivo co-transfer model that infant T cells generate greater numbers of lung-homing effector cells to influenza infection compared to adult T cells in the same host, due to augmented TCF-1 downregulation and T cell receptor (TCR)-mediated signaling. Importantly, infant T cells show increased sensitivity to low antigen doses, originating at the interface between T cells and antigen-bearing accessory cells–through actin-mediated mobilization of signaling molecules to the immune synapse. This enhanced signaling was also observed in human infant versus adult T cells. Our findings provide a mechanism for how infants control pathogen load and dissemination, important for designing developmentally-appropriate strategies for promoting immune responses at this vulnerable life stage.

scholarly journals Retrograde migration supplies resident memory T cells to lung-draining LN after influenza infection

2020 ◽  
Vol 217 (8) ◽  
Author(s):  
J. Michael Stolley ◽  
Timothy S. Johnston ◽  
Andrew G. Soerens ◽  
Lalit K. Beura ◽  
Pamela C. Rosato ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Memory T Cells ◽  
Influenza Infection ◽  
Granzyme B ◽  
Lymphatic Vessels ◽  
Cd8 T Cell ◽  
Lung Infection ◽  
Cell Responses ◽  
Resident Memory T Cells

Numerous observations indicate that resident memory T cells (TRM) undergo unusually rapid attrition within the lung. Here we demonstrate that contraction of lung CD8+ T cell responses after influenza infection is contemporized with egress of CD69+/CD103+ CD8+ T cells to the draining mediastinal LN via the lymphatic vessels, which we term retrograde migration. Cells within the draining LN retained canonical markers of lung TRM, including CD103 and CD69, lacked Ly6C expression (also a feature of lung TRM), maintained granzyme B expression, and did not equilibrate among immunized parabiotic mice. Investigations of bystander infection or removal of the TCR from established memory cells revealed that the induction of the TRM phenotype was dependent on antigen recognition; however, maintenance was independent. Thus, local lung infection induces CD8+ T cells with a TRM phenotype that nevertheless undergo retrograde migration, yet remain durably committed to the residency program within the draining LN, where they provide longer-lived regional memory while chronicling previous upstream antigen experiences.

Author response for "White matter lesions in multiple sclerosis are enriched for CD20 dim CD8 + tissue‐resident memory T cells"

2020 ◽  
Author(s):  
Cheng‐Chih Hsiao ◽  
Nina L. Fransen ◽  
Aletta M.R. den Bosch ◽  
Kim I.M. Brandwijk ◽  
Inge Huitinga ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
White Matter ◽  
Memory T Cells ◽  
White Matter Lesions ◽  
Author Response ◽  
Resident Memory T Cells

Author response for "Circulating memory CD8 + T cells are limited in forming CD103 + tissue‐resident memory T cells at mucosal sites after reinfection"

2020 ◽  
Author(s):  
Felix M. Behr ◽  
Ammarina Beumer‐Chuwonpad ◽  
Natasja A.M. Kragten ◽  
Thomas H. Wesselink ◽  
Regina Stark ◽  
...  
Keyword(s):  
T Cells ◽  
Memory T Cells ◽  
Author Response ◽  
Resident Memory T Cells
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